Pharmacology and the Liver

Question 1

What is Metabolism?

Answer 1

The process by which tissue enzymes (principally in the liver - hepatic metabolism) catalyze the chemical conversion of a frequently lipid soluble drug to an often less actvie and more polar form that is readily extreted from the body.

Question 2

What is Excretion?

Answer 2

The processes that remove the drug, or its metabolites, from the body (principally the kidneys - renal excretion), but other routes may be important for specific agents.

Question 3

What is a drugs ‘Therapeutic window’?

Answer 3

To achieve an effect a drug must reach a critical concentraion in the plasma (i.e. Minimum Effective Concentration; MEC) but ideally be well below that causing significant unwanted effects (i.e. Maximum Tolerated Concentration; MTC)

This is the Therapeutic window.

TR = MTC/MEC

High ration = Safe drugs

Low ration= Unsafe drugs

Question 4

What is Dosing to Steady State?

Answer 4

At steady state (ss): rate of drug administration = rate of drug elimination

Rate of administration and elimination are equal

Question 5

What is a loading dose?

Answer 5

Loading dose is an initial higher dose of a drug given at begining of course treatment before stepping down to a lower maintenance dose

Question 6

What is the main organ of drug metabolism?

Answer 6

The LIVER (hepatic metabolism)

Question 7

What happens to drugs given orally?

Answer 7

Drugs given orally are usually absorbed in the small intestine and enter the portal system to travel to the liver, where they may be extensively metabolised

• a process called First Pass Metabolism

Question 8

What are the 2 important effects of Drug metabolism?

Answer 8

1. Drug is made more hydrophillic - hastens its excretion by the kidneys
2. Metabolites are usually less active than parent drug

Question 9

The LIVER is involved in 2 types of reactions:

• Phase 1 reactions
• Phase 2 reactions

what are these

Answer 9

Phase 1 reactions

• Involve biotransformation of a drug to a more polar metabolite
• By introducing or unmasking a functional group e.g. -OH
• Oxidations are most common reactions - catalyzed by an important class of enzymes the mixed function oxidases with low substrate specificity

Phase 2 reactions

• Drugs / metabolites not polar enough to be excreted rapidly by the kidneys
• Usually occur in the liver and involve conjugation of a drug or its phase 1 metabolite with an endogenous substance

Resulting conjugates are almost always less active and polar molecules readiky excreted by the kidneys